Neutralization of SARS-CoV-2 by destruction of the prefusion Spike
Author:
Huo Jiandong, Zhao Yuguang, Ren Jingshan, Zhou Daming, Duyvesteyn Helen ME, Ginn Helen M, Carrique Loic, Malinauskas Tomas, Ruza Reinis R, Shah Pranav NM, Tan Tiong Kit, Rijal Pramila, Coombes Naomi, Bewley Kevin, Radecke Julika, Paterson Neil G, Supasa Piyasa, Mongkolsapaya Juthathip, Screaton Gavin R, Carroll Miles, Townsend Alain, Fry Elizabeth E, Owens Raymond J, Stuart David IORCID
Abstract
SummaryThere are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding would facilitate conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.HighlightsCR3022 neutralises SARS-CoV-2Neutralisation is by destroying the prefusion SPIKE conformationThis antibody may have therapeutic potential alone or with one blocking receptor attachment
Publisher
Cold Spring Harbor Laboratory
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